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Immuno-Oncology for the Oncology Nurse
*Funding for development of this activity was provided by an independent educational grant from Bristol-Myers Squibb.
Introduction to Immunotherapy
The Immune Response: Terminology
Immunity:
• The body’s ability to resist disease
• Ability of the body to respond to foreign substances (microbes and noninfectious molecules)
Immune system:
• Network (cells, proteins, tissues, organs and molecules) that works together to defend the body against attacks by foreign invaders.
Immune response:
• Coordinated reaction of cells and molecules of theimmune system
(G. P. Dunn & Okada, 2015)
The Immune System: Self vs Non-Self• The key to a functional immune system is the ability to distinguish between self
and non-self. - Cells carry self marker molecules (SELF).
- Cells carry markers that are not recognized as self (FOREIGN) → immune response
• Antigens trigger the immune response.- Microbe (e.g., virus)
- Part of a microbe
Tumor antigens are recognized as foreign by the immune system
and initiate an immune response.
Innate Immunity Adaptive Immunity
MacrophagesDendritic
EosinophilNeutrophil
Basophil Natural Killer Cell
T Cell
T Cell
B CellAntibodies
Natural Killer Cell
CD4+ T Cell CD8+ T Cell
Antigen-Specific: Adaptive
Develops slowly and provides a more specialized defense against infections
Two types of adaptive response:
• Humoral immunity: antibodies
• Cell mediated: T lymphocytes
Non-Specific: Innate
Speed NonspecificLimited duration
Lack immunologic
memory
Inflammation is one of the first responses of innate immunity.
Enhances adaptive immune response
through presentation of antigens
Images used with permission from the Cancer Research Institute.
AntibodiesBind to antigens and mark cells for attack and destruction.
B CellsRelease antibodies to
defend against threats.
CD8+ Killer T CellsSeek out and destroy
cancer cells.
CytokinesHelp immune cells communicate and
coordinate the right response.
Dendritic CellsDigest foreign cells and present their
proteins to immune cells for destruction.
CD4+ Helper T CellsSend “signals” to other immune cells (B cells, CD8+ T cells) to make them more efficient.
Regulatory T CellsProvide checks and balances to ensure
the immune system doesn’t overreact.
MacrophagesEngulf and destroy harmful cells and
present antigens to other immune cells.
Natural Killer CellsIdentify and eliminate
cells that fail to produce self-MHC class molecules.
Images used with permission from the Cancer Research Institute.
AntibodiesBind to antigens and mark cells for attack and destruction.
B CellsRelease antibodies to
defend against threats.
CD8+ Killer T CellsSeek out and destroy
cancer cells.
CytokinesHelp immune cells communicate and
coordinate the right response.
Dendritic CellsDigest foreign cells and present their
proteins to immune cells for destruction.
CD4+ Helper T CellsSend “signals” to other immune cells (B cells, CD8+ T cells) to make them more efficient.
Regulatory T CellsProvide checks and balances to ensure
the immune system doesn’t overreact.
MacrophagesEngulf and destroy harmful cells and
present antigens to other immune cells.
Natural Killer CellsIdentify and eliminate
cells that fail to produce self-MHC class molecules.
Images used with permission from the Cancer Research Institute.
AntibodiesBind to antigens and mark cells for attack and destruction.
B CellsRelease antibodies to
defend against threats.
CD8+ Killer T CellsSeek out and destroy
cancer cells.
CytokinesHelp immune cells communicate and
coordinate the right response.
Dendritic CellsDigest foreign cells and present their
proteins to immune cells for destruction.
CD4+ Helper T CellsSend “signals” to other immune cells (B cells, CD8+ T cells) to make them more efficient.
Regulatory T CellsProvide checks and balances to ensure
the immune system doesn’t overreact.
MacrophagesEngulf and destroy harmful cells and
present antigens to other immune cells.
Natural Killer CellsIdentify and eliminate
cells that fail to produce self-MHC class molecules.
Images used with permission from the Cancer Research Institute.
AntibodiesBind to antigens and mark cells for attack and destruction.
B CellsRelease antibodies to
defend against threats.
CD8+ Killer T CellsSeek out and destroy
cancer cells.
CytokinesHelp immune cells communicate and
coordinate the right response.
Dendritic CellsDigest foreign cells and present their
proteins to immune cells for destruction.
CD4+ Helper T CellsSend “signals” to other immune cells (B cells, CD8+ T cells) to make them more efficient.
Regulatory T CellsProvide checks and balances to ensure
the immune system doesn’t overreact.
MacrophagesEngulf and destroy harmful cells and
present antigens to other immune cells.
Natural Killer CellsIdentify and eliminate
cells that fail to produce self-MHC class molecules.
Images used with permission from the Cancer Research Institute.
AntibodiesBind to antigens and mark cells for attack and destruction.
B CellsRelease antibodies to
defend against threats.
CD8+ Killer T CellsSeek out and destroy
cancer cells.
CytokinesHelp immune cells communicate and
coordinate the right response.
Dendritic CellsDigest foreign cells and present their
proteins to immune cells for destruction.
CD4+ Helper T CellsSend “signals” to other immune cells (B cells, CD8+ T cells) to make them more efficient.
Regulatory T CellsProvide checks and balances to ensure
the immune system doesn’t overreact.
MacrophagesEngulf and destroy harmful cells and
present antigens to other immune cells.
Natural Killer CellsIdentify and eliminate
cells that fail to produce self-MHC class molecules.
Images used with permission from the Cancer Research Institute.
AntibodiesBind to antigens and mark cells for attack and destruction.
B CellsRelease antibodies to
defend against threats.
CD8+ Killer T CellsSeek out and destroy
cancer cells.
CytokinesHelp immune cells communicate and
coordinate the right response.
Dendritic CellsDigest foreign cells and present their
proteins to immune cells for destruction.
CD4+ Helper T CellsSend “signals” to other immune cells (B cells, CD8+ T cells) to make them more efficient.
Regulatory T CellsProvide checks and balances to ensure
the immune system doesn’t overreact.
MacrophagesEngulf and destroy harmful cells and
present antigens to other immune cells.
Natural Killer CellsIdentify and eliminate
cells that fail to produce self-MHC class molecules.
Immunotherapy Principles
Cancer cells are different than healthy cells.
Malignant tumor
Immunoediting: Cancer and Immunity
Cancer Progression
The Cancer Immunity CycleRelease of cancer cell antigens
(1)Cancer antigen
presentation
(2)
Priming and activating
(3)
Trafficking of T cells to
tumor
(4)
Infiltration of T cells into
tumor
(5)
Recognition of cancer by T
cells
(6)
Killing of cancer cells
(7)
(Chen & Mellman, 2013)
Types of Immunotherapy
Monoclonal Antibodies
• Tumor-targeting mAbs
• Boost immune stimulation pathways.
Adoptive Cell Transfer
• Living immune cells modified to trigger an immune response
Vaccines/Oncolytic Viruses
• Harness memory cell function of the immune system to create sustained immunity.
Checkpoint Inhibitors
• Immunomodulatory mAbs
• De-suppress the immune response (“release the brakes”).
Cytokines
• Interferons and interleukins
• Set in motion a general immune response, activating a wide range of immune cells.
Types of Immunotherapy
Monoclonal Antibody (mAb): Basic Structure
Monoclonal Antibodies: Function
Flag cancer cellsfor destruction.
Block growth signals and receptors.
Deliver other anticancer agents to the site of the tumor.
Some Common Monoclonal Antibody TargetsTarget Mechanism Example Agents Applications
in Cancer
CD20 Transmembrane protein that serves as a calcium channel implicated in activation, proliferation, and differentiation of B cells; present in the majority of B-cell NHLs and CLL; targeting CD20 leads to rapid cell lysis
rituximab, obinutuzumab, ofatumumab
NHL, CLL
CD22 Role in establishing a baseline level of B-cell inhibition; helps maintain homeostasis in humoral immunity; expressed in majority of B-cell ALL
inotuzumab, ozogamicin
ALL
HER2 Transmembrane receptor tyrosine kinase; overexpressed in some breast cancers
pertuzumab, trastuzumab
Breast
EGFR Regulates epithelial tissue development; targeting can inhibit signaling pathways leading to cell lysis and induce an immune response against cells with binding receptors
cetuximab Colorectal, lung
Vaccines in CancerCancer
Vaccines
Tumor cell
Antigen
Dendritic
Vector-based
Oncolytic Viruses: Triggering the Immune Response
Oncolytic virus
Normal cell Virus infects but cannot
replicate Unharmed
Tumor cell Virus infects and
replicates.
Tumor cell lysis causing
release of viral particles
and tumor antigens
Virus infects
other tumor
cells.
Released
antigens
promote anti-
tumor immune
response.
(Chen & Mellman, 2013)
Checkpoint Inhibitor Therapy: Immune Checkpoints
• Immune checkpoints are a part of a healthy immune system.
• Regulate immune function and prevent overstimulation.
• Provide a mechanism for tumor cells to evade T-cell recognition.
• Blocking negative immune regulators (checkpoints) may give the human immune system the power to fight cancer.
Checkpoint Receptors in T-Cell Regulation
Immune Checkpoint Inhibition AgentsCytotoxic T Lymphocyte Antigen 4 inhibition (CTLA-4)
• ipilimumab
PD-1 inhibition
• nivolumab
• pembrolizumab
• cemiplimab-rwlc
PD-L1 inhibition
• atezolizumab
• avelumab
• durvalumab
Impact of Modification of T-cell Activation: Immune-Related Adverse Events (irAEs)
“Immune-related toxicity can attack virtually every organ system.”
- John A. Thompson, MD
Encephalitis,
hypophysitisUveitis
Thyroiditis,
hypo-/hyperthyroidism
Pneumonitis,
myocarditis
Nephritis, adrenal
insufficiency
Hepatitis,
pancreatitis,
autoimmune
diabetes
Colitis,
enteritis
Rash, vitiligo
Arthralgia, neuropathy
Thrombocytopenia;
anemia; vasculitis
CAR T-Cell Therapy: Engineering a Patient’s Immune Cells to Fight Cancer
• Chimeric antigen receptor (CAR) T cells are genetically modified autologous T cells that are used to produce an anticancer effect.
• Patient’s T cells are modified to target cancer cells.
• Chimeric antigen receptor is constructed to bind with a target on the cancer cell.
• CAR T cells may also include a molecule that stimulates the T cell to increase immune response.
• Currently, these cells are designed to target a single surface antigen.
Target Drug Clinical Application(s)
CD-19 Tisagenlecleucel ALL, DLBCL
CD-19 Axicabtageneciloleucel
B-cell lymphoma
CAR T-Cell Therapy
Image from the National Cancer Institute
(Anderson et al., 2019; Neelapu, 2018)
Cytokine Release Syndrome (fever, fatigue,
hypertension/tachycardia, nausea, capillary leak, cardiac/renal/hepatic
dysfunction)C
yto
kin
e
Time
Neurologic Toxicity (confusion, delirium,
aphasia, seizure)
“On-target, off-tumor”
Toxicity
CAR T cell
Normal B cell
CD19
B cell aplasia
Malignant B cell
CD19
Tumor cell aplasia
CAR Anaphylaxis/AllergyImmune responses to mouse-derived and/or recombinant proteins
CAR T-Cell Therapy: Adverse Events
Immune-Related Adverse Events (irAEs)
Immunotherapy
Targeted therapy
Chemotherapy
Radiation
Immunotherapy works differently than other therapies.
15%-90% of patients will experience
some grade of irAE while receiving
immunotherapy.
Onset/Predictability of irAEsCan depend on the organ system affected and the type of immunotherapy
More immediate irAEs include hypersensitivity reactions, CRS, and TLS.
Onset may be delayed (months or even years after therapy).
Patients may have a prolonged duration for these adverse events compared to the pattern typically seen with chemotherapy.
irAE Assessment and Management
Early Identification
Grading of Toxicity
Multidisciplinary Assessment
Collaborative Management
(Connolly, Bambhania, & Naidoo, 2019)
Guidelines for irAE Management
ASCO/NCCN Guideline SITC Guidelines ESMO
(Brahmer, 2018; Naidoo, 2017)
Consider holding ICI.
Imaging
Pulse oximetry
Hold ICI.
Pulm consult
Infectious/malignant workup
Consider empiric antibiotics.
Prednisone 1-2 mg/kg/day
Close monitoring
Discontinue ICI permanently.
Admission
Infectious/malignant workup
Empiric antibiotics
Methylprednisolone 1-2
mg/kg/day
Consider TNF, IVIG, or
mycophenolate mofetil for
refractory.
Pneumonitis
Grade 1 Mild Grade 2 Moderate Grade 3-4 Severe
Management Recommendations
Refractory/Severe irAEs
Colitis
Guillain-Barre
syndrome
Hepatitis
Transverse myelitis
Myasthenia gravis
Encephalitis
Myocarditis
These irAEs can become life-threatening or fatal and
often require IV corticosteroids and admission.
Late/chronic irAEs
Endocrinopathies: adrenal
hypophysitis
Endocrinopathies: adrenal
insufficiency
Endocrinopathies: thyroid
dysfunction
Endocrinopathies: hyperglycemia
Rheumatic: inflammatory
arthritis
These irAEs typically occur within 3-6 months. However, they may
occur at any time, even after therapy is discontinued.
• Comorbidities/autoimmune disorders
• Baseline corticosteroids
• Opportunistic infections
• Combination therapy
Special Considerations
(Abdel-Wahab, 2018; Johnson, 2016)
• Telehealth/ triage management
• Stay up to date
• Educate patients early and often
• Side effects of corticosteroids
• Treatment response time
Nursing Considerations and Patient Education
(Abdel-Wahab, 2018; Johnson, 2016)
Most irAEs can be managed effectively if assessed and treated early!
Care Coordination
• Patient engagement, encourage communication
• Educate emergency clinicians, PCP/FNPs, and hospitalists on assessment and treatment of irAEs.
• Oncology urgent/acute care
• ER algorithm
(Handley, 2018)
Immunotherapy Tools
• Wallet card
• Patient diaries
• Baseline symptom assessment forms
• Survivorship care plans
• Drug package insert
• National guidelines
• Care step pathways
irAE Management: Key Takeaways
Remain vigilant.Educate yourself
and peers to
recognize irAEs.
Early
recognition and
prompt intervention
Hospitalization may
be necessary for
severe or refractory
irAE.
Patient/caregiver
education is a
vital component.
Reporting Adverse Events
Role of the Oncology Nurse
Package Inserts: Did You Know?
1. Which patients are typically included in phase I-III clinical trials that support FDA approval?
2. What informs the adverse event incidence rates posted in package inserts?
3. How often are package inserts updated?
Resources for Drug-Related Information
• Drugs@FDA• www.accessdata.fda.gov/script
s/cder/daf/
• NIH’s DailyMed• https://dailymed.nlm.nih.gov/dai
lymed/
Where to Report Immunotherapy Adverse Events
How do we make this
decision?
FDA
Case reports
Medical
record
(Bristol-Myers Squibb, 2018; Wiley, Galiato, Dickman, &
Winklejohn, 2018)
Safe Handling Considerations
What is a hazardous drug?
(Jorgenson & Rinehart, 2015; NIOSH, 2016)
Carcinogenicity
Teratogenicity
Reproductive toxicity
Organ toxicity at low doses
Genotoxicity
Mimic chemical structure/toxicity
What precautions are needed?
Assess the environmentWear
gloves.
Prepare drug using
BSC.
Respiratory protection
Robust surface cleaning
Hand washing
Handle with care.
(de Lemos et al.,
2018; Jorgenson &
Rinehart, 2015;
Langford, n.d.)
Immuno-Oncology for the Oncology Nurse
*Funding for development of this activity was provided by an independent educational grant from Bristol-Myers Squibb.